Medicinal compositions adhering to stomach/duodenum

ABSTRACT

The present invention provides a gastric and/or duodenal adhesive pharmaceutical composition obtained by coating a composition, which comprises a medicament acting at the stomach and/or duodenum and one or more of ingredients selected from water insoluble polymers, polyglycerin fatty acid esters, lipids and waxes, with a polymer having adhesive capacity onto the surface of the mucosa of a digestive tract under acid conditions and separates from the mucosa of the digestive tract in neutral or alkaline conditions. This composition adheres only to the mucosa of the stomach and/or duodenum and releases the medicament over long hours so that sufficient effects are available by a small amount of the medicament.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition whichadheres only to a gastric mucosa and duodenal mucosa and is controlledin the release of its medicament.

BACKGROUND ART

When effective use of a medicament is considered, a preparationcontrolled in the release of the medicament thereof, particularly, asustained release preparation has great advantages such as decrease inthe frequency of administration, maintenance of the blood level for apredetermined time and the like, because it can continuously release themedicament over long hours. Sustained release preparations havetherefore been investigated from various aspects.

Since the medicament of a sustained release preparations is mainlyabsorbed at the intestine, many of the preparations are designed togradually release the medicament while they pass through the wholedigestive tract. On the contrary, preparations designed to exhibit theirefficacy not after adsorbed by the intestine but topically at thestomach or duodenum are not so many.

As a preparation intended to cause the medicament to act in the stomach,reported have been a preparation having intragastric retentionheightened by imparting it with a floating property (Daviss S S et al.Pharm. Res. 208-213(1986)), a preparation whose contact ratio to thesurface of a mucosa has been improved by increasing the specific gravityof it (Devereux J E et al. Pharmacol, 42, 500-501(1990)) and the like.These preparations however are not sufficient in retention.

In addition, a preparation which adheres onto the mucosa of a digestivetract by gelation of a polymer, which has been incorporated in thepreparation, with water has been proposed (Japanese Patent ApplicationLaid-Open No. Hei 5-132416). This preparation however lacks in adhesionselectivity to an intended digestive tract so that it is impossible toadhere this preparation only to the gastric and duodenal mucosae.

An object of the present invention is therefore to provide a preparationwhich adheres only to the gastric and duodenal mucosa, is controlled inthe release of its medicament and has excellent pharmacological effectsselectively for the stomach and duodenum.

DISCLOSURE OF THE INVENTION

With the foregoing in view, the present inventors have carried out anextensive investigation. As a result, it has been found that bycontrolling the release of a medicament by an ingredient selected fromwater insoluble polymers, polyglycerin fatty acid esters, lipids andwaxes, and imparting the medicament with selective adhering capacityonly to the gastric and duodenal mucosae by using a polymer whichadheres to the surface of the mucosa of a digestive tract under acidconditions but does not adhere under neutral or alkali conditions, themedicament acts on the gastric and duodenal mucosa over long hours butquickly excreted from the intestine, which makes it possible to providea preparation exhibiting high pharmacological action at a lowconcentration of the medicament, leading to the completion of thepresent invention.

The present invention therefore provides a gastric and/or duodenaladhesive pharmaceutical composition obtained by coating a composition,which contains a medicament exhibiting action in the stomach and/orduodenum and an ingredient selected from water insoluble polymers,polyglycerin fatty acid esters, lipids and waxes, with a polymer whichhas adhering capacity to the surface of the mucosa of a digestive tractunder acid conditions but separates from the mucosa of the digestivetract under neutral or alkaline conditions.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the relation between the particle size of apreparation and its adhesion ratio to cells.

FIG. 2 illustrates the relation between pH and adhesion.

FIG. 3 illustrates transition of a medicament to gelatin.

FIG. 4 illustrates eradication effects.

FIG. 5 illustrates the eradication effects of preparations different inrelease time.

BEST MODES FOR CARRYING OUT THE INVENTION

Although no particular limitation is imposed on the polymer which hasadhering capacity to the surface of a gastric and/or duodenal mucosaunder acid conditions and separates from the mucosa of a digestive tractunder neutral or alkaline conditions (said polymer will hereinafter becalled “pH-dependent adhesive polymer”), polymers which are soluble in asolution of at least pH 4 and have an anionic group are preferred.Examples of such a pH-dependent adhesive polymer include:

(1) Natural polymers: purified shellac and white shellac; and

(2) Synthetic polymers:

Cellulose derivative polymers: hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate trimellitate, cellulose acetate phthalate,etc.,

Acrylic polymers: polymers obtained from acrylic acid and/or methacrylicacid, polymers obtained from acrylic acid and/or methacrylic acid and acarboxylic ester, etc. and

Polyvinyl alcohol type polymers: polyvinyl acetate phthalate, etc.

As the pH dependent adhesive polymers used in the present invention,those having a carboxyl group are particularly preferred, with thoseobtained from acrylic acid and/or methacrylic acid being more preferredand those obtained from acrylic acid and/or methacrylic acid and acarboxylic ester being still more preferred. Examples of the carboxylicester used herein include acrylic esters and methacrylic esters such asmethyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate,n-butyl acrylate, isobutyl acrylate, t-butyl acrylate, 2-hydroxyethylacrylate, 2-hydroxypropyl acrylate, methyl methacrylate, ethylmethacrylate, n-propyl methacrylate, isopropyl methacrylate,2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, n-butylmethacrylate, isobutyl methacrylate and t-butyl methacrylate.

Among them, a methacrylic acid-methyl methacrylate copolymer ispreferred, with that having a methacrylic acid content of 20 to 60%, forexample, Eudragit L100 or S100 being particularly preferred.

These pH dependent adhesive polymers may be used either singly or incombination.

In the present invention, the ingredient selected from water insolublepolymers, polyglycerin fatty acid esters, lipids and waxes (which mayhereinafter be called “water-insoluble ingredient”) is an ingredient forcontrolling the release of active ingredients.

No particular limitation is imposed on the water insoluble polymers usedin the present invention insofar as they are sustained release basesordinarily employed for preparations. These polymers may be used eithersingly or in combination. As such polymers, following ones may bementioned by way of example.

Cellulose type polymers: crystalline cellulose, ethyl cellulose,hydroxymethylcellulose phthalate, hydroxymethylcellulose acetatesuccinate, carboxymethylethyl cellulose, cellulose acetate phthalate,[etc.] Among them, ethyl cellulose is particularly preferred.

No particular limitation is imposed on the polyglycerin fatty acidesters used in the present invention and fatty acid esters ofpolyglycerin such as di-, tri- or higher-glycerin may be used. As thefatty acid portion of the polyglycerin fatty acid esters, C₈₋₃₀ fattyacids are preferred, while as the polyglycerin portion, diglycerin toeicosaglycerin are preferred.

Specific examples of the polyglycerin fatty acid ester includediglyceryl monostearate, tetraglyceryl monostearate, hexaglycerylmonostearate, decaglyceryl monostearate, tetraglyceryl tristearate,decaglyceryl tristearate, tetraglyceryl pentastearate, hexaglycerylpentastearate, hexaglyceryl monooleate, decaglyceryl monooleate,triglyceryl dioleate, tetraglyceryl dioleate, tetraglyceryl pentaoleate,hexaglyceryl pentaoleate, triglyceryl dilinoleate, tetraglyceryldilinoleate, hexaglyceryl dilinoleate, tetraglyceryl monopalmitate,hexaglyceryl monopalmitate, decaglyceryl monopalmitate, tetraglyceryltripalmitate and hexaglyceryl tripalmitate.

Examples of the lipid used in the present invention include higher fattyacids and salts thereof, higher alcohols and fatty acid glycerin estersand those of the wax include waxes and hydrocarbons. Examples of thehigher saturated fatty acid or salt thereof include C₈₋₃₀ fatty acidsand salts thereof such as stearic acid, magnesium stearate and aluminumstearate. Examples of the higher alcohol include C₁₀₋₂₄ aliphaticalcohols such as stearyl alcohol and cetyl alcohol. As the fatty acidglycerin ester, not only triglycerides with a fatty acid but alsomonoglycerides and diglycerides therewith may be used. Examples of thewaxes include carnauba wax and bees wax, while those of the hydrocarboninclude microcrystalline wax and paraffin.

The above-described water-insoluble ingredients, that is,water-insoluble polymers, polyglycerin fatty acid esters, lipids andwaxes, may be used either singly or in combination.

With a view to freely controlling the releasability of the medicamentfrom a preparation, a water soluble polymer may be added in any ratio tothe above-described water-insoluble ingredient. Examples of such apolymer include polyethylene glycol, hydroxyethyl cellulose,hydroxypropyl cellulose, aminoalkyl methacrylate copolymers andpolyvinylacetal diethylaminoacetate.

In order to freely control the releasability in the present invention,the water soluble polymer is preferably added in an amount ranging from0.1 to 60 wt. % to the above-described water-insoluble ingredient.

As the medicament used in the present invention, medicaments which actin the stomach or duodenum are suited. Examples of such medicamentsinclude antiacids, gastric mucosa protectors, H₂ blockers, proton pumpinhibitors (PPIs), antibiotics and urease inhibitors.

Examples of the antiacid used in the present invention include magnesiumhydroxide and aluminum magnesium silicate.

Examples of the gastric mucosa protector used in the present inventioninclude methyl methionine sulfonyl chloride (MMSC), ecabet sodium,sucralfate and cetraxate hydrochloride.

Examples of the H₂ blocker used in the present invention includefamotidine, cimetidine, roxatidine acetate and ranitidine.

Examples of the PPIs used in the present invention include omeprazoleand lansoprazole.

Examples of the urease inhibitor used in the present invention includeacetohydroxamic acid and caprylohydroxamic acid.

Examples of the antibiotic used in the present invention includeanti-Helicobacter pylori active substances, bismuth salts and quinolonetype compounds, of which anti-Helicobacter pylori active substances arepreferred. Examples of the anti-Helicobacter pylori active substanceinclude penicillin type antibiotics (such as amoxicillin andampicillin), macrolides (such as erythromycin and clarithromycin) andtetracycline type antibiotics (such as tetracycline, minocycline andstreptomycin). Among these antibiotics, penicillin type antibiotics arepreferred, with amoxicillin (which will hereinafter be abbreviated as“AMOX”) having high antibacterial property against Helicobacter pyloribeing particularly preferred.

In the composition of the present invention, the content of themedicament may be determined as needed depending on the nature of themedicament or preparation. Usually, a content of 0.01 to 95 wt. % or sois preferred, with a range of from 0.1 to 90 wt. % being particularlypreferred. The using amount of the water-insoluble ingredient may bedetermined depending on the nature of the ingredient, release time ofthe medicament or the like. It is however preferred to incorporate it inan amount of 0.1 to 95 wt. % in the composition, with 1 to 60 wt. %being particularly preferred. The pH-dependent adhesive polymer ispreferably incorporated in an amount of 0.1 to 95 wt. % in thecomposition, with 1 to 50 wt. % being particularly preferred.

To the composition of the present invention, ordinarily employedadditives used for the preparation of a solid pharmaceutical may beadded. Examples include following ones:

(1) Excipient: lactose, corn starch, talc, powdered sugar, lightanhydrous silicic acid, calcium carbonate, magnesium carbonate, etc.

(2) Binder: starch, sucrose, gelatin, powdered acacia, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, pullulan, dextrin,etc.

(3) Plasticizer: polyethylene glycol, triethyl citrate, etc.

In addition, colorants, corrigents, adsorbents, antiseptics, humectantsand antistatic agents can be used as additives. The amount of such anadditive may be determined as needed within an extent neither impairingpH-dependent adhesion to the gastric mucosa nor having adverse effectson the releasability of the medicament.

The composition of the present invention comprises a medicament, anadditive if necessary, and the above-described insoluble ingredient andit has been coated with a pH-dependent adhesive polymer. Here, thecomposition comprising a medicament, a necessary additive and theabove-described water-insoluble ingredient may be a composition having amedicament or medicament-additive mixture coated with theabove-described water-insoluble ingredient or a matrix containing themedicament, necessary additive and the above-described water-insolubleingredient as a mixture. The former one is however preferred. The term“coating” as used herein means not only the uniform coating of the wholesurface of a particle but also partial coating of the surface of theparticle.

Although the release time of the medicament from the preparation may bedetermined freely in consideration of the properties of the medicamentto be selected or the like, continuous and longer release time isdesired in order to fully exhibit the properties of the preparation,that is, to adhere to the gastric mucosa and allow the medicament todirectly act thereon. In addition, the release of the medicament isdesirably completed while the preparation has still adhered to andretained in the gastric mucosa. Influences of gastric juice, metabolismof the gastric epitheliocytes, meal and the like must of course be takeninto consideration. The release time of the medicament from thepreparation is desired to be 2 to 8 hours, judging from theabove-described factors. The release time may be controlled by a ratioof the water-insoluble ingredient to a water soluble polymer, amount ofthe water-insoluble ingredient or the like.

The particle size of the pharmaceutical composition of the presentinvention is preferred to fall within a range of 30 to 300 μm from theviewpoint of adhesion to the gastric and/or duodenal mucosa, with arange of 75 to 300 μm, moreover 100 to 250 μm being particularlypreferred.

In the case where the pharmaceutical composition of the presentinvention is a preparation coated with the above-describedwater-insoluble ingredient, it is prepared, for example, by formingmedicament-containing particles by a conventionally employed granulatoror the like and then coating the particles with the above-describedwater-insoluble ingredient and pH dependent adhesive polymersuccessively. For granulation, fluidized bed granulation, high sheargranulation, extrusion granulation or the like can be adopted. Forcoating, conventionally employed method such as pan coating or fluidizedbed coating can be adopted. For the coating agent in the form of asolution or dispersion containing water or an organic solvent, spraycoating can also be adopted.

In the case where the composition containing a medicament and theabove-described water-insoluble ingredient is in the form of a matrix,it can be prepared by dissolving the above-described water-insolubleingredient in a suitable organic solvent, kneading the resultingsolution with the medicament, and then drying and pulverizing thekneaded mass, or dissolving the above-described water-insolubleingredient containing the medicament in a suitable solvent, dispersingthe resulting solution in a solution immiscible with the solvent andthen evaporating the solvent by heating to form particles; and thencoating the particles with a pH-dependent adhesive polymer.

There is no particular limitation imposed on the nature of the organicsolvent. Examples include alcohols such as methanol, ethanol andisopropanol, ketones such as acetone and halogenated hydrocarbons suchas chloroform and dichloromethane. In the coating agent or matrix, theabove-described additive or the like may be incorporated.

EXAMPLES

The present invention will hereinafter be described more specifically byexamples and tests. It should however be borne in mind that the presentinvention is not limited by these examples.

Example 1

In accordance with the formulation shown in Table 1, a gastric and/orduodenal mucosa adhesive preparation was prepared using a fluidized-bedcoating machine. Namely, to 3000 g of anhydrous calciumhydrogenphosphate (average particle size: 150 μm), a solution of 75 g ofriboflavin phosphate in 3 liters of water was sprayed and dried,followed by spraying and coating of a solution of 400 g of ethylcellulose in 4 liters of ethanol. After drying, a solution of 500 g of amethacrylic acid-methyl methacrylate copolymer (“Eudragit L100”, tradename) and 50 g of triethyl citrate in 5 liters of ethanol was sprayedfor coating, whereby a yellow gastric and/or duodenal mucosa adhesivepreparation 1 was prepared.

Comparative Example 1

In a similar manner to Example 1, a solution of 75 g of riboflavinphosphate in 3 liters of water was sprayed to 3000 g of anhydrouscalcium hydrogenphosphate (average particle size: 150 μm) and dried,followed by coating only with a solution of 400 g of ethyl cellulose in4 liters of ethanol, whereby Comparative preparation 1 was obtained.

TABLE 1 Adhesive Comparative preparation 1 preparation 1 Anhydrouscalcium hydrogen- 3000 g 3000 g phosphate (“Fujikarin SG”, trade name)Riboflavin phosphate 75 g 75 g Ethyl cellulose 400 g 400 g Methacrylicacid-methyl methacrylate copolymer (“Eudragit L100”, trade name) 500 g —Triethyl citrate 50 g —

Referential Example 1

In accordance with the formulation shown in Table 2, gastric and/orduodenal mucosa adhesive compositions were prepared. Namely, 20 g of amethacrylic acid-methyl methacrylate copolymer (“Eudragit L100”, tradename) and 2 g of triethyl citrate were dissolved in 50 ml of ethanol,followed by the addition of 25 g of a medicament and 75 g of anexcipient. The resulting mixture was thoroughly mixed under heating to60° C. and then dried. The dried mixture was pulverized, followed byclassification, whereby preparations having average particle sizes ofabout 30, 70, 100, 150, 200, 270, 325, 350 and 400 μm, respectively wereobtained.

TABLE 2 Barium sulfate 25 g Corn starch 75 g Methacrylic acid-methyl 20g methacrylate copolymer (“Eu- dragit L100”, trade name) Triethylcitrate 2 g (Ethanol) 50 ml

Example 2

In a fluidized-bed granulator, 250 g of AMOX and 250 g of an excipient,out of the ingredients shown in Table 3, were charged, followed byspraying thereto a solution of 40 g of ethyl cellulose in 400 ml ofethanol and granulation. Then, the resulting granules were coated with asolution of 150 g of ethyl cellulose in 1.5 liters of ethanol and thenwith a solution of 125 g of a methacrylic acid-methyl methacrylatecopolymer (“Eudragit L100”, trade name) and 25 g of triethyl citrate in1.5 liters of ethanol, whereby a preparation was formed. The resultingpreparation was classified, whereby spherical fine particles passingthrough not 150 mesh but 80 mesh (which will hereinafter be abbreviatedas “80/150 mesh”) were obtained as Preparation (1). In the next place,41.9 g of AMOX and 458.1 g of an excipient were charged in afluidized-bed granulator, followed by granulation. The resultinggranules were coated in a similar manner to that described forPreparation (1), whereby Preparation (2) was obtained. In the thirdplace, 41.9 g of AMOX and 458.1 g of an excipient were charged in afluidized-bed granulator and granulated in a similar manner to thatdescribed for Preparation (2), followed by coating with a solution of112 g of ethyl cellulose and 38 g of polyethylene glycol 6000 in 1.5liters of ethanol for the control the releasability. The methacrylicacid-methyl methacrylate copolymer (“Eudragit L100”, trade name) wascoated in a similar manner to that described for Preparation (1) or (2),whereby Preparation (3) was obtained. In the fourth place, 250 g of AMOXand 250 g of an excipient were charged in a fluidized-bed granulator,followed by granulation in a similar manner to (1). The resultinggranules were coated with ethyl cellulose and then with a solution ofmethacrylic acid-methyl methacrylate copolymers (“Eudragit L100”, tradename: 93.7 g, “Eudragit S100”, trade name: 31.3 g) and 25 g of triethylcitrate in 1.5 liters of ethanol, whereby Preparation (4) was obtained.

TABLE 3 (1) (2) (3) (4) AMOX 250 g 41.9 g 41.9 g 250 g Corn starch 250 g250 g 250 g 250 g Mannitol — 208.1 g 208.1 g — Ethylcellulose 190 g 190g 152 g 190 g PEG6000 — — 38 g — Methacrylic acid-methyl methacrylatecopolymers: (“Eudragit L100”, 125 g 125 g 125 g 93.7 g trade name)(“Eudragit S100”, — — — 31.3 g trade name) Triethyl citrate 25 g 25 g 25g 25 g Release time (hour) 6 6 2 6

Comparative Example 2

By using a polymer forming a gel with water, said polymer beingdescribed in Japanese Patent Application Laid-Open No. Hei 5-132416, apreparation adhesive onto the mucosa of a digestive tract was prepared.Described specifically, 85 g of stearic acid was dissolved at 70° C.,followed by the addition of 15 g of an acrylic acid type polymer(“Hibiswako 104”, trade name). After thorough mixing for 10 minutes, theresulting mixture was cooled and solidified. The resulting solid wassubjected to pulverization and classification, whereby a preparationhaving a particle size of about 150 μm was prepared.

Test 1 Investigation of intragastric retention brought by a pH dependentadhesive polymer

Preparations obtained in Example 1 and Comparative Example 1 were eachsuspended in an amount of 10% (W/V) in the JP first liquid. To rats (SDrats, 8 weeks old) fasted for 24 hours, 2 ml of the resulting suspensionwas administered. Each of one hour and three hours after theadministration, the stomach was enucleated and retention of thepreparation in the stomach was investigated. As a result, the retentionof the yellow preparation of Example 1 in the stomach each of one hourand three hours after the administration was confirmed, while theretention of the yellow preparation of Comparative Example 1 was notconfirmed after one hour. From the results, it has been confirmed thatthe addition of a methacrylic acid-methyl methacrylate copolymer isnecessary for the retention of the preparation in the gastric mucosa.

Test 2 Investigation on the adhesion depending on a particle size

Preparations obtained in Referential Example 1, which differed in theparticle size, were each suspended in an amount of 10% (W/V) in the JPfirst liquid. Two ml of the resulting suspension was administered tohuman fibroblasts which had been cultured on a plastic slip until theconfluent condition. By being left over standstill for one minute, thepreparation was adhered to the cells. After adhesion, the plastic slipwas washed in the JP first liquid. Then, the weight of the preparationremained on the plastic slip was measured and the amount of thepreparation adhered was calculated. In addition, from the amountadhered, the covered area of the preparation was calculated inaccordance with the following formula as an indication of adhesion ofthe preparation to cells.

<Calculation formula>

particle size : r, specific gravity of the preparation:

d, amount adhered: W

Weight per particle: w 4/3 xπx (r/2)³ x d

Number of particles adhered: N=W/w

Area covered by one particle: s=πx (r/2 )²

Total covered area: S=N x s

The results are shown in FIG. 1. From the results, concerning theadhesion of the preparation to cells, no change was recognized in theadhesion of the particles having a particle size up to 200 μm, gradualdeterioration in adhesion was recognized in the particles having aparticle size greater than 200 μm and adhesion was not recognized in theparticles having a particle size of 350 μm or greater. From the abovefinding, it has been confirmed that pH-dependent adhesion of thepreparation occurs within a particle size up to 300 μm or so andconstantly high adhesion is available when the particle size is up to200 μm or so.

Test 3

The adhesion to the human fibroblasts in each of solutions different inpH was studied using the preparation of Referential Example 1 containinga methacrylic acid-methyl methacrylate copolymer and having a particlesize of 150 μm and the comparative preparation containing an acrylicacid type polymer and prepared in Comparative Example 2. The results areshown in FIG. 2.

From the results, the preparation containing a methacrylic acid-methylmethacrylate copolymer exhibited good adhesion in JP1 (pH 1.2) but noadhesion was observed in a physiological saline adjusted to pH 6. Thecomparative preparation containing an acrylic acid type polymer, on theother hand, exhibited no difference in adhesion depending on pH. Fromthe above finding, it has been recognized that the adhesion brought by amethacrylic acidmethyl methacrylate copolymer depends on pH and has hightopical selectivity.

Test 4

Transition of medicament by mucoadhesion

A solidified 20% gelatin was placed in a solution as a gastric mucosamodel. To the gelatin, 50 mg (1 mg in terms of riboflavin phosphate) ofthe gastric and/or duodenal mucosa adhesive preparation prepared inExample 1 and 1 mg of riboflavin phosphate were each administered,followed by stirring at 25 rpm to remove a concentration gradient. After1 hour and 3 hours, amounts of the medicament transferred to the gelatinwere measured, respectively. The results are shown in FIG. 3.

From the results, higher transition was confirmed in the gelatinadministered with the gastric and/or duodenal mucosa adhesivepreparation compared with that administered with the solution,indicating that more effective pharmacological action can be attainedand dosage can be reduced by adhering the preparation directly to thestomach and/or duodenum and releasing the medicament from thepreparation.

Test 5

Effects of AMOX-containing gastric and/or duodenal mucosa adhesivepreparation

Each of the AMOX-containing gastric and/or duodenal mucosa adhesivecompositions [(1), (2) and (4) in Table 3] prepared in Example 2 wassuspended in a 0.1% tragacanth solution for use as apreparation-administering solution. In a similar tragacanth solution,AMOX powder was suspended for use as an administering solution. A ddYmouse fasted for 24 hours was orally and endogastrically infected withHelicobacter pylori ATCC 43504 (which will hereinafter be abbreviated as“HP”; 10⁹ viable count x 3/mouse). After 27 days, the respectivesolutions of preparations and solution were adjusted to contain AMOX inamounts of 0.1 mg/kg (preparation (2)) and 1 mg/kg (preparations (1) and(4)) and then orally administered for 5 straight days. From the mouse,its stomach was excised 24 hours after the final administration and asolution of the disrupted stomach was inoculated on an HP selectivemedium. After incubation for 8 days under microaerophilic conditions,the viable count was measured. The viable count of HP is shown in FIG.4. From the results, it has been confirmed that compared with the groupadministered with the solution-administering group, the groupadministered with the AMOX containing gastric and/or duodenal adhesivepreparation exhibited higher eradication effects.

Test 6

Eradication effects of AMOX-containing gastric and/or duodenal mucosaadhesive preparation depending on release time

The AMOX-containing gastric and/or duodenal mucosa adhesive preparations[(2) and (3) in Table 3] prepared in Example 2 were each suspended in a0.1% tragacanth solution. The resulting suspension was adjusted tocontain AMOX in an amount of 0.1 mg/kg, followed by administration for 5straight days to a ddY mouse infected with HP in a similar manner toTest 4. The viable count was measured as in Test 5 and results are shownin FIG. 5. From the results, two AMOX-containing gastric and/or duodenalmucosa adhesive preparations were recognized to have higher eradicationeffects than the solution. Moreover, the preparation (2) with a longerrelease time of AMOX (6 hours) was recognized to have higher eradicationeffects than the preparation (3) with a shorter AMOX release time (2hours). From the above finding, it has been recognized that effectiveeradication can be carried out by controlled release of a medicament.

Example 3

In 20 ml of ethanol, 6 g of a methacrylic acid-methyl methacrylatecopolymer (“Eudragit L100”, trade name) and 1.2 g of triethyl citratewere charged and dissolved thoroughly. To the resulting solution, 8 g oftetraglyceryl monostearate was added. After drying, the resultingmixture was subjected to granulation and classification, whereby apreparation having an average particle size of 150 μm was obtained.

Example 4

In 20 ml of ethanol, 6 g of a methacrylic acid-methyl methacrylatecopolymer (“Eudragit L100”, trade name) and 1.2 g of triethyl citratewere charged and dissolved thoroughly. The resulting solution was mixedwith 8 g of stearic acid. After drying, the mixture was granulated andclassified, whereby a preparation having an average particle size of 150μm was obtained.

The adhesion of the preparations obtained in Examples 3 and 4 weretested in a similar manner to Test 3. As a result, it has beenrecognized that the adhesion of these preparations depends on pH and hashigh topical selectivity.

CAPABILITY OF EXPLOITATION IN INDUSTRY

The gastric and/or duodenal mucosa adhesive pharmaceutical compositionaccording to the present invention exhibits pH dependent adhesion sothat it adheres directly onto the mucosa of a digestive tract under acidconditions and has high retention in the digestive tract, which makes itpossible to release the medicament from the preparation directly to themucosa of the stomach and/or duodenum; and it also exhibits a controlledrelease property, which permits continuous release of the medicament andeffective transition of the active ingredients into the gastric and/orduodenal mucosa. Sufficient effects can be attained by a smaller dosageso that the preparation has high safety and permits effective use of theactive ingredients.

What is claimed is:
 1. An adhesive pharmaceutical composition obtainedby coating a composition, which comprises a medicament acting at thestomach or duodenum and a water insoluble cellulose polymer (I), with asecond composition consisting essentially of a polymer (II) having anadhesive capacity onto the surface of the mucosa of a digestive tractunder acid conditions and separates from the mucosa of the digestivetract in neutral or alkaline conditions, wherein said polymer (II) isobtained from an acrylic acid, a methacrylic acid or a mixture thereof,and a carboxylic ester.
 2. A pharmaceutical composition according toclaim 1, wherein the medicament has been coated with one or more ofingredients selected from the water insoluble polymers, polyglycerinfatty acid esters, lipids and waxes.
 3. A pharmaceutical compositionaccording to claim 1, wherein the polymer having adhesive capacity ontothe surface of the mucosa of a digestive tract under acid conditions andseparating from the mucosa of the digestive tract under neutral oralkaline conditions is soluble in a solution of at least pH 4 and has ananionic group.
 4. A pharmaceutical composition according to claim 1,wherein the medicament is selected from the group consisting ofantiacids, gastric mucosa protectants, H₂ blockers, proton pumpinhibitors (PPIs), antibiotics, and urease inhibitors.
 5. Thepharmaceutical composition as claimed in claim 1, wherein the polymer(II) is a methacrylic acid-methacrylate copolymer.
 6. The pharmaceuticalcomposition according to claim 1, wherein said polymer (I) is ethylcellulose.
 7. The pharmaceutical composition according to claim 5,wherein said polymer (I) is ethyl cellulose.
 8. The pharmaceuticalcomposition as claimed in claim 1, wherein the polymer (II) is solublein a solution of at least 4 pH.
 9. The pharmaceutical compositionaccording to claim 1, wherein the carboxylic ester is selected from thegroup consisting of methyl acrylate, ethyl acrylate, n-propyl acrylate,isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, t-butylacrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl acrylate, methylmethacrylate, ethyl methacrylate, n-propyl methacrylate, isopropylmethacrylate, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate,n-butyl methacrylate, isobutyl methacrylate and t-butyl methacrylate.10. The pharmaceutical composition according to claim 1, wherein thepolymer (II) has a methacrylic acid content of from 20 to 60%.
 11. Thepharmaceutical composition according to claim 1, wherein the secondcomposition further consists essentially of one or more ingredientsselected from the group consisting of an excipient, a binder, aplasticizer, a colorant, a corrigent, an adsorbent, an antiseptic, ahumectant and an antistatic agent.
 12. The pharmaceutical compositionaccording to claim 11, further consisting essentially of an excipientselected from the group consisting of lactose, corn starch, talc,powdered sugar, light anhydrous silicic acid, calcium carbonate andmagnesium carbonate.
 13. The pharmaceutical composition according toclaim 11, further consisting essentially of a binder selected from thegroup consisting of sucrose, gelatin, powdered acacia, polyvinylpyrrolidone, pullulan and dextrin.
 14. The pharmaceutical compositionaccording to claim 11, further consisting essentially of a plasticizerselected from the group consisting of polyethylene glycol and triethylcitrate.